Vascular Endothelial Growth Factor A Contributes to Increased Mammalian Respiratory Epithelial Permeability Induced by Pasteurella multocida Infection

Lin Lin; Jie Yang; Dajun Zhang; Qingjie Lv; Fei Wang; Peng Liu; Mixue Wang; Congcong Shi; Xi Huang; Wan Liang; Chen Tan; Xiangru Wang; Huanchun Chen; Brenda A Wilson; Bin Wu; Zhong Peng

doi:10.1128/spectrum.04554-22

Vascular Endothelial Growth Factor A Contributes to Increased Mammalian Respiratory Epithelial Permeability Induced by Pasteurella multocida Infection

Microbiol Spectr. 2023 Mar 14;11(2):e0455422. doi: 10.1128/spectrum.04554-22. Online ahead of print.

Authors

Lin Lin¹, Jie Yang¹, Dajun Zhang¹, Qingjie Lv¹, Fei Wang¹, Peng Liu¹, Mixue Wang¹, Congcong Shi¹, Xi Huang¹, Wan Liang¹, Chen Tan¹, Xiangru Wang¹, Huanchun Chen¹, Brenda A Wilson², Bin Wu¹, Zhong Peng^{1

3}

Affiliations

¹ State Key Laboratory of Agricultural Microbiology, The Cooperative Innovation Center for Sustainable Pig Production, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
² Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA.
³ Hubei Hongshan Laboratory, Wuhan, China.

Abstract

Pasteurella multocida infection can cause significant zoonotic respiratory problems in both humans and animals, but little is known about the mechanisms used by P. multocida to invade and cross the mammalian respiratory barrier. In this study, we investigated the influence of P. multocida infection on the dysfunction of the respiratory epithelial barrier. In vivo tests in mouse infection models demonstrated that P. multocida infection significantly increased epithelial permeability and increased the expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in murine tracheae and lungs. In murine lung epithelial cell (MLE-12) models, P. multocida infection decreased the expression of tight junctions (ZO-1) and adherens junctions (β-catenin and E-cadherin) proteins but induced the activation of hypoxia-inducible factor 1α (HIF-1α) and VEGFA signaling. When the expression of HIF-1α is suppressed, the induction of VEGFA and ZO-1 expression by P. multocida infection is decreased. We also found that intervention of HIF-1α and VEGFA signaling affected infection outcomes caused by respiratory bacteria in mouse models. Most importantly, we demonstrate that P. multocida infection increases the permeability of human respiratory epithelial cells and that this process is associated with the activation of HIF-1α and VEGFA signaling and likely contributes to the pathogenesis of P. multocida infection in humans. IMPORTANCE The mammalian respiratory epithelium forms the first line of defense against infections with P. multocida, an important zoonotic respiratory pathogen. In this study, we found that P. multocida infection increased respiratory epithelial permeability and promoted the induction of the HIF-1α-VEGFA axis in both mouse and murine cell models. Similar findings were also demonstrated in human respiratory epithelial cells. The results from this study provide important knowledge about the pathogenesis of P. multocida causing infections in both animals and humans.

Keywords: HIF-1α; Pasteurella multocida; VEGFA; hypoxia-inducible factor 1α; mammalian respiratory epithelial permeability; pathogenesis; vascular endothelial growth factor A.